Worldwide Protein Data Bank www.wwpdb.org

1. Worldwide Protein Data Bank www.wwpdb.org

2. wwPDB • Formalization of current working practice • Members • RCSB (Research Collaboratory for Structural Bioinformatics) • PDBj (Osaka University) • Macromolecular Structure Database (EBI) • MOU signed July 1, 2003 • Announced in Nature Structural Biology November 21, 2003

3. Mission Maintain a single archive of macromolecular structural data that is freely and openly available to the global community

4. Guidelines and Responsibilities • All members issue PDB ID’s and serve as distribution sites for data • One member is the archive keeper (RCSB) • Manage entry ID’s • Sole write access • All format documentation publicly available • Strict rules for redistribution of PDB files • All sites can create their own web sites

5. Maintain Format Standards • PDB • PDB Exchange (mmCIF) • Mechanism for extension based on new demands • PDBML • Derived from mmCIF • All entries converted to XML • Automatic translation from mmCIF data files and dictionaries • 3-styles of translation released • PDBML: the representation of archival macromolecular structure data in XML. (2005) Bioinformatics 21, pp. 988-992

6. Progress Report • Publications • Exhibit stand at IUCr Meeting • New web site with pointers to member groups • DVD distribution with time stamp • Notification of availability of PDBML to computational biologists • Many phone conferences and regular email exchanges; staff exchange visits • Significant progress on uniformity and integration

10. Web of Science Citations Gupta, K; Thomas, D; Vidya, SV; et al. Detailed protein sequence alignment based on Spectral Similarity Score (SSS). BMC BIOINFORMATICS, 6: Art. No. 105. Westbrook, J; Ito, N; Nakamura, H; et al. PDBML: the representation of archival macromolecular structure data in XML. BIOINFORMATICS, 21 (7): 988-992 Kinoshita, K; Nakamura, H. Identification of the ligand binding sites on the molecular surface of proteins PROTEIN SCIENCE, 14 (3): 711-718 Brooksbank, C; Cameron, G; Thornton, J. The European Bioinformatics Institute's data resources: towards systems biology. NUCLEIC ACIDS RESEARCH, 33: D46-D53 Sp. Iss. SIMulder, NJ; Apweiler, R; Attwood, TK; et al. InterPro, progress and status in 2005.NUCLEIC ACIDS RESEARCH, 33: D201-D205 Sp. Iss. SI Velankar, S; McNeil, P; Mittard-Runte, V; et al. E-MSD: an integrated data resource for bioinformatics NUCLEIC ACIDS RESEARCH, 33: D262-D265 Sp. Iss. SIKersey, P; Bower, L; Morris, L; et al. Integr8 and Genome Reviews: integrated views of complete genomes and proteomes. NUCLEIC ACIDS RESEARCH, 33: D297-D302 Sp. Iss. SI Ragno, R; Frasca, S; Manetti, F; et al. HIV-reverse transcriptase inhibition: Inclusion of ligand-induced fit by cross-docking studies. JOURNAL OF MEDICINAL CHEMISTRY, 48 (1): 200-212Ragno, R; Artico, M; De Martino, G; et al. Docking and 3-D QSAR studies on indolyl aryl sulfones. Binding mode exploration at the HIV-1 reverse transcriptase non-nucleoside binding site and design of highly active N-(2-hydroxyethyl)carboxamide and N-(2-hydroxyethyl)carbohydrazide derivatives. JOURNAL OF MEDICINAL CHEMISTRY, 48 (1): 213-223Kleywegt, GJ; Harris, MR; Zou, JY; et al. The Uppsala Electron-Density Server. ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 60: 2240-2249 Part 12 Sp. Iss. 1 Chen, Y; Kortemme, T; Robertson, T; et al. A new hydrogen-bonding potential for the design of protein-RNA interactions predicts specific contacts and discriminates decoys. NUCLEIC ACIDS RESEARCH, 32 (17): 5147-5162 2004 Yang, HW; Guranovic, V; Dutta, S; et al. Automated and accurate deposition of structures solved by X-ray diffraction to the Protein Data Bank ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 60: 1833-1839 Opella, SJ; Marassi, FM. Structure determination of membrane proteins by NMR spectroscopy. CHEMICAL REVIEWS, 104 (8): 3587-3606 Cantley, M. Life sciences and GMOs: Still an uninsurable risk? GENEVA PAPERS ON RISK AND INSURANCE-ISSUES AND PRACTICE, 29 (3): 490-502 Nagpal, A; Valley, MP; Fitzpatrick, PF; et al. Crystallization and preliminary analysis of active nitroalkane oxidase in three crystal forms. ACTA CRYST SECT D60: 1456-1460 Tsuchiya, Y; Kinoshita, K; Nakamura, H. Structure-based prediction of DNA-binding sites on proteins using the empirical preference of electrostatic potential and the shape of molecular surfaces PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 55 (4): 885-894

11. Time-stamped Record of PDB • 36 Gbytes of data from the PDB FTP site on DVD • Includes: • PDB format entries • mmCIF format entries • PDBML format entries (3 flavors) • Experimental data • Dictionary, schema and format documentation • 8 DVD set

12. PDB Uniformity • Ligands: RCSB • Sequence, taxonomy, entities: MSD • Citations: PDBj

13. PDB & Ligand Chemistry

14. Ligands • Currently ~5700 small molecules in library • 80,000 instances in the PDB • Before remediation • No stereo information • Not all names could be resolved into unique structure • Unsure how well definitions equal instances • Errors in deposited data? • Errors in annotation?

15. Strategy • Stereo calculation for 80,000 ligands • MSD - CACTVS • Stereo signatures and SMILES strings for every instance • Loaded into MSDChem - accessible for data mining AND systematic checking of errors • Provided representative stereo SMILES to RCSB for comparison • RCSB - OpenEye • Stereo SMILES for every instance • MSD SMILES standardization and comparison • Literature-based SMILES generation • RCSB - CAS, SciFinder, Belstein Commander • Verification of chemical identity and CAS number for 5000 ligand definitions

16. Systematic comparison • Ligand definitions which disagreed between MSD and RCSB efforts: • Checked for chemical correctness • Chemdraw, Ligand-Depot, Marvin, individual instances • Majority of differences • Stereo isomers of instances (a-glucose vs b-glucose) • Bond order disagreements (aromatic vs Kekule)

17. Results • Ligand dictionary now • Unique stereo SMILES strings • Names can be converted to unique structures • Remaining ~200 are organometallic or other unusual chemistry - SMILES doesn’t work • Representative coordinates • Public update by end of year • Started • Annotation of library <=> instance differences • Gathering instances that need new definitions

18. PDB & Sequence and Taxonomy

19. Sequence and Taxonomy • All analysis is based on chains • 6745 mmCIF’s have no UniProt value • 262 mmCIF’s have a different UniProt value than MSD • 1666 mmCIF’s have Taxonomy different than MSD • 845 mmCIF's have no Taxonomy data

20. 6745 mmCIF’s do not have a UniProt value • Chains have no DBREF • Chains have GenBank or SwissProt reference • GB and SWS are redundant and/or obsolete Example: 1A02 DBREF 1A02 N 399 678 GB 1353774 U43341 399 678 DBREF 1A02 F 140 192 SWS P01100 FOS_HUMAN 140 192 DBREF 1A02 J 267 318 SWS P05412 AP1_HUMAN 257 308 ACTION: use the MSD UniProt value

21. 262 mmCIF’s have a UniProt value different to MSD Example: 1a2c PDB file:DBREF 1A2C I 355 364 SWS P28501 ITHA_HIRME 55 64 mmCIF file:_struct_ref_seq.pdbx_db_accession P09945

22. 262 mmCIF’s have a UniProt value different to MSD 1a2c NGDFEEIPEEYL P28501 …TGEGTPKPQSHNDGDFEEIPEEYLQ RCSB P09945 …TGEGTPNPESHNNGDFEEIPEEYLQ MSD ACTION: These have to be individually checked *

23. 1666 mmCIF’s with Taxonomy differences to MSD • 1305 - no valid name • 463 - chimera or strange • mmCIF's have 2 species names on the same line • counted as a difference Example: 4mon SOURCE 2 ORGANISM_SCIENTIFIC: DIOSCOREOPHYLLUM CUMMINISII DIELS; MSD: Dioscoreophyllum cumminsii tax.id. 3457 ACTION: Use the MSD taxid

24. 845 mmCIF's no taxonomy data Examples: 9api 9gpb 9ins 9ldb 9ldt ACTION: Take the MSD Taxid

25. Mismatched Entities between MSD and RCSB ACTION: Check meaning of CHAIN and number of chains in entries concerned

26. ACTION: pass to RCSB The corrected mmCIF categories _entity_src_nat _entity_src_gen (this is confirmation only) _struct_ref _struct_ref_seq _struct_ref_seq_dif For each matched _entity (of type protein polymer) _entity_poly_seq Suggested new items: _entity_src_gen.pdbx_taxid _entity_src_gen.pdbx_host_taxid _entity_src_nat.pdbx_taxid

27. PDB & Citations

28. Citations • ~32,000 of the original PDB entries have incomplete primary citations • Accurate primary citations are key archival data, are essential for linking to other databases, and for future semantic web • Historically, BNL had an archive of the reprints of the primary citations, but they were not complete • The three wwPDB members have made independent efforts to remediate the primary citation information

29. Citations • Before remediation • Many PDB entries without primary citations (544 entries on May 10, 2005) • Some PDB entries have erroneous information in the primary citations • Many PDB entries lack PubMed identifiers for primary citations (4,300 entries on May 10, 2005) • “To be published” citations require update (2,798 entries on May 10, 2005)

30. Strategy (1) • Systematic analysis of the current situation • Incomplete citations (data on May 10, 2005) Consensus citation information (e.g. Journal abbrev., volume, start-page, end-page, year, PubMed ID) in mmCIF files, EBI-MSD database, and PDBj xPSSS annotated database, is completely identical 16,897 No information about primary citations or “To be published” 3,342 Non-consensus cases Lack of agreement in PubMed ID 10,466 958 Missing PubMed ID

31. Strategy (2) • Construction of a new literature archive A new literature archive is being constructed at PDBj by collecting primary citations, producing electronic copies as PDF files, and storing them in a TByte hard disk, by using the Osaka University Library with 12,000 journals. Currently, ~7,000 PDF files for the primary citations have been curated.

32. Cooperation in the wwPDB • PDBj effort:Incomplete citations and citations without PubMed IDs have been manually annotated at PDBj by searching literature databases (PubMed and SciFinder scholar) and reading papers and dissertations for (958 + 3342) 4,258 entries • EBI-MSD effort:Citations with PubMed IDs have been confirmed at EBI-MSD for 10,466 entries • RCSB-PDB effort:Searching their literature archive for the citations that may exist in the PDB physical archive

33. Results • For citations without PubMed IDs (4,258 entries): • Established the correct primary citations with PubMed IDs: 1,211 • Established the correct primary citations without PubMed IDs: 349 • Structural genomics primary citations may not be published: 693 • Confirmed that the citation is “Unpublished” by the authors: 73 • Obsolete or replaced ID after May 10, 2005: 65 • Stopped remediation for Theoretical models: 383 • total: 2,774 • (The remaining 1,526 are still being annotated at PDBj) • For citations with PubMed IDs (10,466) • MSD-EBI annotated: 6,773 • RCSB annotated: 3,634 • PDBj annotated: 59

34. Next Action • The remediation of the primary citation will be completed • A new electronic literature archive will be created • The remediated citation information will be added to the archival files in PDB, mmCIF, and PDBML formats • Experience gained in this remediation effort will be used to shape future annotation of citation data • The original citation information in the legacy data should be retained

35. NMR Data

36. NMR Depositions • Chemical shifts and other primary experimental data deposited to BMRB • Coordinate and meta data deposited to all wwPDB sites

37. BMRB Interactions • RCSB • ADIT-NMR for joint BMRB PDB deposition • Will require BMRB to issue PDB ID • PDBj at Osaka (Prof. Hideo Akutsu) • Mirror deposition and processing of NMR experimental data • EBI (Wim Vranken) • RECOORD-recalculations of NMR structures using normalized and filtered PDB restraint files

38. Collaboration between BMRB and PDBj • Mirror deposition processing of NMR experimental data for BMRB with two curators from August 2005 • Establishment of a reliable data flow and a common annotation system in the BMRB/PDBj database management system • Cooperation with RIKEN-Structural Genomics group to find a smooth data deposition scheme both for PDBj and BMRB • Development of ontology for the solid-state NMR for biological molecules

39. EM Data

40. wwPDB and EM Current database based on • ftp://ftp.ebi.ac.uk/pub/databases/emdb/doc/XML-schema/emd_v1_4.xsd Developed under the European Commission as the IIMS, QLRI-CT-2000-31237 • http://www.ebi.ac.uk/msd/projects/IIMS.html

41. wwPDB and EM • http://www.ebi.ac.uk/msd-srv/emdep/ • http://www.ebi.ac.uk/msd-srv/emsearch/

42. wwPDB and EM • The data definition dictionaries also covered extensions for deposition of fitted coordinates to the PDB • This is the result of an extensive collaboration between the EBI/IIMS partners and the RCSB, in particular with Monica Chagoyen (Madrid), Richard Newman (EBI) and John Westbrook (RCSB) • http://mmcif.pdb.org/dictionaries/mmcif_iims.dic/Index/ • http://iims.ebi.ac.uk/3dem_pdb.html

43. wwPDB and EM • Support for EMdep has continued in Europe with the establishment of the PF6 Network of Excellence 3D-EM on New Electron Microscopy Approaches for Studying Protein Complexes and Cellular Supramolecular Architecture • www.3dem-noe.org

44. wwPDB and EM • Collaboration with US to further develop the data definitions required to enhance EMdep and EMdb, and to investigate how to improve the linking of PDB fitted coordinates from EM reconstructions with deposited maps. • RCSB workshop (October 23-24, 2004) • http://rcsb-cryo-em-development.rutgers.edu/workshop/ • co-sponsored by the Computational Center for Biomolecular Complexes (C2BC) • http://ncmi.bcm.tmc.edu/ccbc

45. wwPDB and EM New extensively revised dictionary resulted from the work of many contributors. It will be the basis of further software workshop to be held at the EBI October 12-14, 2005. http://rcsb-cryo-em-development.rutgers.edu/mmcif_iims.dic-rev/Categories/

46. wwPDB and EM Proposal for Joint RCSB/EBI EM database/data deposition will be submitted in February 2006 to fully integrate EM maps with the PDB fitted coordinates

47. Models

48. Models in the PDB • Ambiguous policies over the years • Revisit decision to remove models

49. The Ambiguities • Define line between “pure” models and models based on data • Large experimental spectrum e.g. X-ray, NMR, EM, SAX, FRET models • Homology models especially as derived from structural genomics • Need a way to archive models that is totally compatible with PDB

50. Finding a solution • Workshop at the RCSB PDB to develop a white paper on models (November 19-20, 2005)